The hypothesis underlying this Program Project is that cell free hemoglobin, suitably modified by structural engineering, will be safe and effective therapy in many clinical situations where red blood cells are indicated. The main goal of the Program Project is to understand the physiological consequences and clinical potential of replacement of red blood cells in the circulation with acellular blood substitutes. Expertise in design, production and testing of new solutions, with academic expertise in several key areas of biochemistry, physiology, molecular biology and clinical medicine will be brought together under this Program Project to focus on specific problems of large scale infusions of acellular red cell substitutes, while simultaneously exploiting emerging technology to shed new light on basic physiological and biochemical problems. The elements of the Program Project reflect the interests of the UCSD faculty, rather than a comprehensive approach to development of blood substitutes. However, the expertise is broad and deep, and nearly all relevant areas will be studied. Core A will coordinate activities of the component projects and cores, manage budget, purchasing, scheduling of meetings and seminars, and provide basic secretarial support. Core B will produce or obtain materials representing various classes of products under development for investigation by the various projects, including both hemoglobin- and perflurocarbon-based oxygen carries; some will be produced in the Program Project, and others will be obtained from other laboratories. The in vitro ligand binding, stability and toxicity will be related to protein structure in Project 1, and the effects on the microcirculation will be studied in Project 2, the heart in Project 3, the kidney in Project 4. Data obtained in these projects will be used in Project 1 for the design of new chemically modified or (by collaboration) mutant derivatives of hemoglobin using computer visualization techniques in Project 1. Each project will have advisors from the UCSD faculty. An executive committee made up of the principal investigators from each project and core that has met monthly for the last year will form the nucleus of a group and will continue to share data, results, and plans for future studies. Internal and external advisory groups of outstanding scientists will be appointed to provide expertise in related fields.